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Ribosomal mistranslation leads to silencing of the unfolded protein response and increased mitochondrial biogenesis


Shcherbakov, Dmitri; Teo, Youjin; Boukari, Heithem; Cortes-Sanchon, Adrian; Mantovani, Matilde; Osinnii, Ivan; Moore, James; Juskeviciene, Reda; Brilkova, Margarita; Duscha, Stefan; Kumar, Harshitha Santhosh; Laczko, Endre; Rehrauer, Hubert; Westhof, Eric; Akbergenov, Rashid; Böttger, Erik C (2019). Ribosomal mistranslation leads to silencing of the unfolded protein response and increased mitochondrial biogenesis. Communications Biology, 2:381.

Abstract

Translation fidelity is the limiting factor in the accuracy of gene expression. With an estimated frequency of 10$^{-4}$, errors in mRNA decoding occur in a mostly stochastic manner. Little is known about the response of higher eukaryotes to chronic loss of ribosomal accuracy as per an increase in the random error rate of mRNA decoding. Here, we present a global and comprehensive picture of the cellular changes in response to translational accuracy in mammalian ribosomes impaired by genetic manipulation. In addition to affecting established protein quality control pathways, such as elevated transcript levels for cytosolic chaperones, activation of the ubiquitin-proteasome system, and translational slowdown, ribosomal mistranslation led to unexpected responses. In particular, we observed increased mitochondrial biogenesis associated with import of misfolded proteins into the mitochondria and silencing of the unfolded protein response in the endoplasmic reticulum.

Abstract

Translation fidelity is the limiting factor in the accuracy of gene expression. With an estimated frequency of 10$^{-4}$, errors in mRNA decoding occur in a mostly stochastic manner. Little is known about the response of higher eukaryotes to chronic loss of ribosomal accuracy as per an increase in the random error rate of mRNA decoding. Here, we present a global and comprehensive picture of the cellular changes in response to translational accuracy in mammalian ribosomes impaired by genetic manipulation. In addition to affecting established protein quality control pathways, such as elevated transcript levels for cytosolic chaperones, activation of the ubiquitin-proteasome system, and translational slowdown, ribosomal mistranslation led to unexpected responses. In particular, we observed increased mitochondrial biogenesis associated with import of misfolded proteins into the mitochondria and silencing of the unfolded protein response in the endoplasmic reticulum.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > General Biochemistry, Genetics and Molecular Biology
Life Sciences > General Agricultural and Biological Sciences
Health Sciences > Medicine (miscellaneous)
Language:English
Date:17 October 2019
Deposited On:07 Jan 2020 10:57
Last Modified:29 Jul 2020 12:08
Publisher:Nature Publishing Group
ISSN:2399-3642
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s42003-019-0626-9
PubMed ID:31637312

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